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NeoReviews Apr 2021With over 400 reported disorders, the skeletal dysplasias represent a myriad of molecularly-based skeletal abnormalities. Arising from errors in skeletal development,... (Review)
Review
With over 400 reported disorders, the skeletal dysplasias represent a myriad of molecularly-based skeletal abnormalities. Arising from errors in skeletal development, the clinical spectrum of disease evolves through an affected individual's life. The naming and grouping of these disorders are ever-changing, but the fundamentals of diagnosis remain the same and are accomplished through a combination of prenatal ultrasonography and postnatal physical examination, radiography, and genetic analysis. Although some disorders are lethal in the perinatal and neonatal periods, other disorders allow survival into infancy, childhood, and even adulthood with relatively normal lives. The foundation of management for an affected individual is multidisciplinary care. Medical advances have offered new insights into reducing common morbidities through pharmacologic means. This review summarizes the normal skeletal development and discusses the 3 most common skeletal dysplasias that can affect the newborn.
Topics: Bone Diseases, Developmental; Female; Humans; Infant, Newborn; Physical Examination; Pregnancy; Radiography; Ultrasonography, Prenatal
PubMed: 33795397
DOI: 10.1542/neo.22-4-e216 -
Ceskoslovenska Patologie 2023We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or... (Review)
Review
We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or lethal phenotypes are identifiable in the prenatal period and the pregnancy can be terminated. Perinatal autopsy and posmortem X-rays are crucial in providing a definitive diagnosis. The number of cases confirmed by genetic testing is increasing. We report our own experience with genetic skeletal disorders based on 41 illustrative fetal and neonatal cases which we encountered over a 10-year period. Thanatophoric dysplasia and osteogenesis imperfecta represent approximately half of the cases coming to autopsy. Achondrogenesis type 2 and hypochondrogenesis, short-rib dysplasia, chondrodysplasia punctata, campomelic dysplasia and achondroplasia are less common. Skeletal dysplasias with autosomal recessive inheritance are the least frequent, e.g. perinatally lethal hypophophatasia, achondrogenesis type 1A, diastrophic dysplasia/atelosteogenesis type 2 or mucolipidosis type 2 (I cell disease).
Topics: Pregnancy; Female; Humans; Osteochondrodysplasias; Thanatophoric Dysplasia; Campomelic Dysplasia; Receptor, Fibroblast Growth Factor, Type 3; Fetus
PubMed: 37468326
DOI: No ID Found -
Seminars in Musculoskeletal Radiology Feb 2021Osteochondrodysplasias are the result of the expression of gene mutations. The phenotypes in osteochondrodysplasias evolve through life, with the possibility that... (Review)
Review
Osteochondrodysplasias are the result of the expression of gene mutations. The phenotypes in osteochondrodysplasias evolve through life, with the possibility that previously unaffected bones may be involved at later stages of growth. Due to the variable time of onset, the diagnosis may be made prenatally, at birth, or later. Certainty in the diagnosis is sometimes only achieved as the patient matures and the disease evolves. Radiographic evaluation is a fundamental part of the diagnostic work-up of congenital skeletal disorders and in most cases the first tool used to arrive at a diagnosis. This review describes the imaging characteristics, specific signs, and evolution of several skeletal dysplasias in which diagnosis may be directly or indirectly suggested by radiologic findings. A definitive accurate diagnosis of a congenital skeletal abnormality is necessary to help provide a prognosis of expected outcomes and to counsel parents and patients.
Topics: Bone and Bones; Diagnostic Imaging; Humans; Musculoskeletal Abnormalities; Osteochondrodysplasias; Phenotype
PubMed: 34020466
DOI: 10.1055/s-0041-1723964 -
Dermatology and Therapy Sep 2019Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider... (Review)
Review
Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider the diagnosis of a genetic hair disorder. Genetic hair disorders are a large group of inherited disorders, many of which are rare. Genetic hair abnormalities in children can be an isolated phenomenon or part of genetic syndromes. Hair changes may be a significant finding or even the initial presentation of a syndrome giving a clue to the diagnosis, such as Netherton syndrome and trichothiodystrophy. Detailed history including family history and physical examination of hair and other ectodermal structures such as nails, sweat glands, and sebaceous glands with the use of dermoscopic devices and biopsy all provide important clues to establish the correct diagnosis. Understanding the pathophysiology of genetic hair defects will allow for better comprehension of their treatment and prognosis. For example, in patients with an isolated hair defect, the main problem is aesthetic. In contrast, when the hair defect is associated with a syndrome, the prognosis will depend mainly on the associated condition. Treatment of many genetic hair disorders is focused on treating the primary cause and minimizing trauma to the hair.
PubMed: 31332722
DOI: 10.1007/s13555-019-0313-2 -
AACE Clinical Case Reports 2020To present a case of pyknodysostosis (PKND), a rare genetic cause of skeletal dysplasia that often goes undiagnosed even in patients with classic features.
OBJECTIVE
To present a case of pyknodysostosis (PKND), a rare genetic cause of skeletal dysplasia that often goes undiagnosed even in patients with classic features.
METHODS
We report a case of PKND that went undiagnosed over many years despite classic features. We performed physical examination, imaging studies, and genetic testing on the patient.
RESULTS
A 21-year-old female presented to endocrinology to establish care. On evaluation, she was noted to have disproportionate short stature and a past medical history notable for bilateral blindness due to optic atrophy secondary to bone enlargement and thickening of the optic nerve canal before age 7 years. She also had a history of foot fractures occurring with ambulation. Her family history was significant for consanguineous parents and relatives with similar clinical features. Physical examination revealed a short, 128-cm tall female with open anterior and mastoid fontanels, mild frontal bossing and micrognathia, evidence of double rows of teeth, and digits of varied length in both hands and feet. Plain radiographs demonstrated diffuse sclerosis and marked cortical thickening of the pelvis, femurs, metacarpals, proximal phalanges, and metatarsals as well as decreased phalangeal length and acro-osteolysis of the hands and feet. Dual energy X-ray absorptiometry demonstrated increased bone mineral density ( scores +2.5 lumbar spine, +3.7 femoral neck, +4.5 total hip). Genetic testing revealed a exon 5-homozygous mutation in the cathepsin K () gene consistent with PKND.
CONCLUSION
Patients with PKND come to medical attention for a variety of reasons but often go undiagnosed even when presenting with classic features due to the rarity of the condition and the overlap with other skeletal dysplasias.
PubMed: 32984533
DOI: 10.4158/ACCR-2020-0169 -
La Revue Du Praticien Nov 2022
Topics: Humans; Fibrous Dysplasia, Polyostotic
PubMed: 36512017
DOI: No ID Found -
Dermatology Reports Aug 2021The ectopic nail (EN) is an additional nail located in an abnormal site. It belongs to the onycho-heterotopia, a rare condition whose pathogenesis is indeterminate. This...
The ectopic nail (EN) is an additional nail located in an abnormal site. It belongs to the onycho-heterotopia, a rare condition whose pathogenesis is indeterminate. This article illustrates the clinical-morphological and dermoscopic points of view, the diagnostic criteria, the possible pathogenesis, and surgical treatment of this pediatric onycho- heterotopia.
PubMed: 34497697
DOI: 10.4081/dr.2021.9068 -
Brain : a Journal of Neurology Feb 2024Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural...
Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.
Topics: Child; Humans; Mice; Animals; Focal Cortical Dysplasia; Epilepsy; TOR Serine-Threonine Kinases; Protein Serine-Threonine Kinases; Seizures; Genetic Therapy; Malformations of Cortical Development; Mammals
PubMed: 38100333
DOI: 10.1093/brain/awad387 -
International Journal of Molecular... Apr 2020Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties... (Review)
Review
Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.
Topics: Animals; Bone Diseases, Developmental; Cartilage; Disease Susceptibility; Energy Metabolism; Extracellular Matrix; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Glycosaminoglycans; Humans; Metabolic Networks and Pathways; Phenotype; Protein Processing, Post-Translational; Proteoglycans; Sulfates
PubMed: 32295296
DOI: 10.3390/ijms21082710 -
Clinical Genetics Apr 2020Ectodermal dysplasias are a family of genodermatoses commonly associated with variants in the ectodysplasin/NF-κB or the Wnt/β-catenin pathways. Both pathways are...
Ectodermal dysplasias are a family of genodermatoses commonly associated with variants in the ectodysplasin/NF-κB or the Wnt/β-catenin pathways. Both pathways are involved in signal transduction from ectoderm to mesenchyme during the development of ectoderm-derived structures. Wnt/β-catenin pathway requires the lymphoid enhancer-binding factor 1 (LEF1), a nuclear mediator, to activate target gene expression. In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. We report two unrelated patients with 4q25 de novo deletion encompassing LEF1, associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. Taurodontism and a particular alveolar bone defect were also observed in both patients. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human. We provide further evidence for LEF1 haploinsufficiency role in ectodermal dysplasia and delineate its clinical phenotype.
Topics: Adult; Animals; Child, Preschool; Ectodermal Dysplasia; Ectodermal Dysplasia 1, Anhidrotic; Female; Haploinsufficiency; Humans; Lymphoid Enhancer-Binding Factor 1; Male; Mice; NF-kappa B; Signal Transduction; Young Adult; beta Catenin
PubMed: 32022899
DOI: 10.1111/cge.13714